Francisella tularensis is a gram-negative, facultative, highly virulent bacterium, which causes the zoonotic disease tularemia. Infection can occur through several routes, but pneumonic tularemia is the most severe clinical form, with a mortality rate up to 60 percent in the absence of treatment. F. tularensis can invade a range of host cells, but its primary target in vivo is the macrophage. Sjostedt, A, Curr. Opin. Microbiol. 6, p. 66-71 (2003). After being phagocytosed by macrophages, this intracellular pathogen can block the fusion of Francisella-containing phagosomes with lysosomes and escape from the phagosome into the cytosol where it multiplies. Following proliferation within macrophages, F. tularensis induces host cell apoptosis or pyroptosis leading to the release of bacteria and subsequent infection of new cells.
Because of the ease with which aerosolized organisms could potentially be deliberately disseminated, inflicting substantial morbidity and mortality on large numbers of people, F. tularensis has been recognized as a potential biological warfare agent and, consequently, has been classified as a Category A bioterrorism agent by the U.S. Centers for Disease Control and Prevention. Unfortunately, the current live attenuated vaccine derived from a type B strain of F. tularensis has serious drawbacks and is of limited utility in the face of a bioterror threat. Oyston et al., Nat. Rev. Microbiol. 2, p. 967-78 (2004). Moreover, it is believed that antibiotic-resistant strains of F. tularensis were created in the early 1990s as biological weapons. Dennis et al., JAMA, 285, p. 2763-73 (2001). Consequently, the development of novel, antibacterial agents against F. tularensis has become an important priority.